ENDOSCOPIC FOLLOW-UP OF RADICALLY RESECTED SUBMUCOSAL ADENOCARCINOMA IN BARRETT’S ESOPHAGUS: INTERIM RESULTS OF AN ONGOING PROSPECTIVE, INTERNATIONAL, MULTICENTER COHORT REGISTRY (PREFER TRIAL)

INTRODUCTION
Current guidelines advise esophagectomy for submucosal esophageal adenocarcinoma (T1b EAC). However, data from retrospective studies suggest that endoscopic follow-up (FU) may be a valid alternative in patients without signs of lymph node metastases (LNM) at baseline. In this international multicenter, prospective cohort study (NCT03222635), we aim to evaluate the safety of a watchful waiting strategy with regular endoscopic FU in patients treated endoscopically for T1b EAC.

METHODS
This ongoing prospective study is conducted in 19 hospitals in Europe and Australia, and aims to include 141 patients with 5-year FU. After radical endoscopic resection of T1b EAC, patients are re-staged with endoscopic ultrasound (EUS) and CT/PET. In the absence of LNM or distant metastases (N0M0), and upon consent for endoscopic FU, patients are included and undergo strict endoscopic FU with gastroscopy and EUS every 3 months during year 1 and 2, every 6 months during year 3 and 4, and at year 5. CT/PET is repeated after 1 year. We divided our cohort into two groups: high-risk (submucosal invasion ≥500um, a/o poorly/undifferentiated tumor (G3-4), a/o lymphovascular invasion (LVI+)), and low-risk if high risk features are absent. Primary outcome parameters are 5-year disease specific survival and overall survival; secondary outcome parameters are rate of LNM and local recurrence.

RESULTS
Since July 2017, 120 patients (100 men, median 68 yrs) were included with a median FU of 22 (IQR 10-32) months: 80 high-risk and 40 low-risk patients. 6 patients (5% [95CI 1.0-9.0]) were diagnosed with LNM (table 1) after median FU of 8 (IQR 5-16) months. Of these 6 patients, 2/6 were referred for neoadjuvant chemo(radio)therapy with esophagectomy (ypT0N0M0, ypT0N1M0), 1/6 underwent esophagectomy only (pT0N2M0), 3/6 underwent selective surgical resection of the tumor-positive LN.

7 patients (6% [95CI 2.0-10.0] were diagnosed with an intra-luminal tumor recurrence not eligible for endoscopic re-treatment after median FU of 7 (IQR 6-15) months. 5 had initial ESD and 2 cap-based EMR. Of these 7 patients, 2/7 underwent esophagectomy (pT1bN0M0, pTisN0M0), 1/7 had neoadjuvant chemoradiotherapy and esophagectomy (ypT1aN0M0), 2/7 underwent chemoradiotherapy only, 1/7 had palliative radiotherapy, 1/7 refused additional treatment. No distant metastases were diagnosed during FU in both cohorts. 6 patients died, all non EAC-related deaths. 3 patients discontinued FU due to old age. 2 patients were lost to FU.

CONCLUSION
The interim analysis from our ongoing prospective study suggest that in patients with radically removed high- or low-risk T1b EAC, without LNM at baseline, a strict endoscopic follow-up protocol is feasible and curative therapy remains possible in those patients who develop LNM (5%) or a local intra-luminal recurrence (6%) during FU. Most patients demonstrate uneventful FU.